Why are hematopoietic stem cells so 'sexy'? on a search for developmental explanation

Abstract

Evidence has accumulated that normal human and murine hematopoietic stem cells express several functional pituitary and gonadal sex hormones, and that, in fact, some sex hormones, such as androgens, have been employed for many years to stimulate hematopoiesis in patients with bone marrow aplasia. Interestingly, sex hormone receptors are also expressed by leukemic cell lines and blasts. In this review, I will discuss the emerging question of why hematopoietic cells express these receptors. A tempting hypothetical explanation for this phenomenon is that hematopoietic stem cells are related to subpopulation of migrating primordial germ cells. To support of this notion, the anatomical sites of origin of primitive and definitive hematopoiesis during embryonic development are tightly connected with the migratory route of primordial germ cells: from the proximal epiblast to the extraembryonic endoderm at the bottom of the yolk sac and then back to the embryo proper via the primitive streak to the aorta-gonado-mesonephros (AGM) region on the way to the genital ridges. The migration of these cells overlaps with the emergence of primitive hematopoiesis in the blood islands at the bottom of the yolk sac, and definitive hematopoiesis that occurs in hemogenic endothelium in the embryonic dorsal aorta in AGM region.

Figure 1

Panel A. A possible reason for the current poor results for clinical expansion of HSCs. It is most likely that the most of the current clinical expansion procedures employ HSCs that are already “rolling downhill” in following a differentiation pathway (left panel). The expansion strategy should be better initiated at the level of VSELs, which are highly quiescent and positioned at the top of the stem cell compartment hierarchy (right panel). Panel B. Proposed developmental interrelationship between PGCs, VSELs, hemangioblasts, HSCs, and EPCs. I propose that migratory primordial germ cells (PGCs), aside from their major role in establishing gametogenesis, may be a source of certain developmentally primitive stem cells (e.g., VSELs) that give rise to hematopoietic stem cells (HSCs) and endothelial progenitor cells (EPCs) and are a source of other tissue-committed stem cells (TCSCs), such as mesenchymal stem cells (MSCs). Specification of VSELs into HSCs and EPCs may involve putative hemangioblast as an intermediate precursor cell. VSEL-derived hematopoiesis may play a role under steady-state conditions in contributing to a pool of long-term repopulating HSCs and/or VSELs may become specified into HSCs during hematopoietic emergency stress situations. In support of this latter notion, the number of proliferating VSELs in BM increases in mice after acute bleeding. Dotted lines – concepts still under investigations.

Figure 1

Panel A. A possible reason for the current poor results for clinical expansion of HSCs. It is most likely that the most of the current clinical expansion procedures employ HSCs that are already “rolling downhill” in following a differentiation pathway (left panel). The expansion strategy should be better initiated at the level of VSELs, which are highly quiescent and positioned at the top of the stem cell compartment hierarchy (right panel). Panel B. Proposed developmental interrelationship between PGCs, VSELs, hemangioblasts, HSCs, and EPCs. I propose that migratory primordial germ cells (PGCs), aside from their major role in establishing gametogenesis, may be a source of certain developmentally primitive stem cells (e.g., VSELs) that give rise to hematopoietic stem cells (HSCs) and endothelial progenitor cells (EPCs) and are a source of other tissue-committed stem cells (TCSCs), such as mesenchymal stem cells (MSCs). Specification of VSELs into HSCs and EPCs may involve putative hemangioblast as an intermediate precursor cell. VSEL-derived hematopoiesis may play a role under steady-state conditions in contributing to a pool of long-term repopulating HSCs and/or VSELs may become specified into HSCs during hematopoietic emergency stress situations. In support of this latter notion, the number of proliferating VSELs in BM increases in mice after acute bleeding. Dotted lines – concepts still under investigations.